This invention relates to a process for preparing thioamines such as 4-(amino-alkylene-thiomethyl)-imidazole. Such compounds, particularly the 4-(2-aminoethylthiomethyl)-imidazoles, have found use as intermediates for preparing commercially important medicinal agents having histamine H.sub.2 -agonist activity. One indication of such activity is the inhibition of gastric acid secretion (see Black et al, Nature 1972, 236-385). An example of one of the end products made from such thioamines is cimetidine, N-cyano-N'-methyl-N"-[5-methyl-4-imidazolyl(methylthio)-ethyl]guanidine, see U.S. Pat. No. 3,950,333.
The thioamine used in one such process is prepared by reaction of cysteamine with the reaction product mixture produced by the electrochemical reduction of imidazole carboxylic esters, such as the reduction of lower alkyl 4-imidazolecarboxylates to give a mixture of the corresponding alcohol and lower alkyl ethers, see U.S. Pat. No. 4,055,573. This patent teaches a method for preparing 4-(hydroxymethyl)-imidazoles in mixture with their lower alkyl ethers by electrochemical reduction in concentrated sulfuric acid in concentrated solutions using standard electrochemical cells with yields up to 80%. Subsequent reaction of the mixed alcohol-alkyl ether with cysteamine hydrochloride produces the corresponding thioamine in about 60% yield. Several of the processes for production of 4-(hydroxymethyl)-imidazoles have the disadvantage of producing a diether of the desired compound which is a bis-(imidazolylmethyl)-ether hydrochloride. This bis-(imidazolylmethyl)-ether represented a yield loss of desired intermediate and an undesirable impurity requiring separation.
The conversion of this bis-(imidazolylmethyl)-ether hydrochloride to the corresponding 4-(hydroxymethyl)-imidazole by acid catalyzed ether cleavage was considered. Further, it was thought to be even more desirable if the bis-(imidazolylmethyl)-ether hydrochloride could be converted to the corresponding 4-(.OMEGA.-amino-alkylene-thiomethyl)-imidazole, i.e., the corresponding thioamine, directly. However, investigation of the chemical literature indicated that classical acid catalyzed ether cleavage required strong acid and produced at least one equivalent of the corresponding halide, sulfate or other acid anion salt. See Fieser et al, Organic Chemistry, 3rd Ed., Reinhold Publishing Co., New York, p. 137 (1956); Jaques et al, J. Chem. Soc. (London), 1964, pp. 2683-89; Daniels et al, J. Org. Chem., 1962, Vol. 27, pp. 4710-11; Patai, The Chemistry of the Ether Linkage, pp. 22-42, Interscience-Wiley, 1967. Further, the stability of the ether linkage to milder conditions and the use of amine salts was thought to be of insufficient strength to cleave the ether linkage and form the thioamine. See Burwell, The Cleavage of Ethers, Chem. Rev., Vol. 54, pp. 635-6 (1954).